Bis(2-[(disubstituted amino)methyl]-1H-indole) compounds

ABSTRACT

Bis(2-[(disubstitutedamino)methyl]-1H-indole) compounds wherein said 2-[(disubstitutedamino)methyl]-1H-indol-3-ylmethylene moieties are linked together through a piperazine or 1,3-dihydro-2H-indol-2-one fragment and acid addition salts thereof which are useful pharmacological agents, especially antifungals, are disclosed. The compounds can be produced by reacting a piperazine or 1,3-dihydro-2H-indole-2-one compound with the appropriate quaternary salt of 2-alkyl-1,2,3,4-tetrahydropyrrolo-[3,4-b]indole.

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to new bis-indoles. More particularly, theinvention relates to new bis-indole compounds of the formula ##STR1##and acid addition salts thereof, and to a method for production of theforegoing compounds, where R¹ and R² are lower alkyl groups, R³ ishydrogen, a lower alkyl group, halogen or a lower alkoxy group and A isa molecular fragment of the formula ##STR2## where R⁴ is hydrogen orlower alkyl. The preferred compounds are those wherein R¹ is methyl, R²is methyl or butyl and R³ and R⁴ are hydrogen.

The term "lower alkyl" is intended to mean an alkyl group of from one tosix carbon atoms, such as methyl, ethyl, butyl, and isopentyl and theterm "lower alkoxy" is intended to mean lower alkyl--O--. The term "acidaddition salt" is intended to mean a salt such as the hydrochloride,sulfate, acetate, benzoate, citrate, hydrobromide, nitrate, etc.preferably the pharmaceutically acceptable salts such as thehydrochloride, sulfate, citrate, etc.

The term "halogen" is intended to mean chlorine, fluorine, iodine orbromine.

In accordance with the invention, the foregoing compounds of formula Iwherein A is ##STR3## can be prepared by reacting a compound of theformula ##STR4## with a compound of the formula ##STR5## wherein R¹, R²,R³ and R⁴ are as previously defined in formula I, and X is loweralkylsulfonate, bromine, chlorine or iodine, preferably iodine. Molarratios of reactants are not critical since the bis indole productappears to be favored. This reaction may be carried out in a polarsolvent such as an alcohol, water or mixtures thereof at temperatures offrom about 50° C. to the reflux temperature of the solvent for periodsof from fifteen minutes up to eight hours. The reaction is preferablyconducted in water at reflux for a period of about two hours. Theaddition of an acid, such as hydrochloric acid converts the above formedfree base to its acid addition salt.

Also in accordance with the invention, the foregoing compounds offormula I wherein A is ##STR6## can be prepared by reacting a compoundof the formula ##STR7## with a compound of the formula ##STR8## in theform of its anion wherein R¹, R², R³ and R⁴ are as previously defined informula I and X is lower alkylsulfate, bromine, chlorine or iodine,preferably iodine. The anion is formed initially by using a strong basesuch as sodium hydride. Molar ratios of reactants are not critical sincethe bis indole product appears to be favored. This reaction may becarried out in an inert polar solvent such as dimethylformamide,dimethylacetamide or mixtures thereof at temperatures of from about 50°C. to about 150° C. for periods of from fifteen minutes up to eighthours. The reaction is preferably conducted in dimethylformamide on asteam bath for a period of about one hour. The addition of an acid, suchas hydrochloric acid converts the above formed free base to its acidaddition salt.

Compounds of the formula II are prepared by reacting a compound of theformula ##STR9## with a compound of the formula

    R.sup.1 X                                                  IV

wherein R¹, R² and R³ are as previously defined. The reaction isconducted in a polar solvent. When employing an alkyl iodide, a rapidreaction takes place at room temperature in an acetone solvent; however,using alkyl chlorides and bromides usually requires higher reactiontemperatures utilizing pressure vessels and reaction times of up totwenty-four hours.

Compounds of the formula III are prepared by reducing a compound of theformula ##STR10## according to procedures reported in the Journal ofOrganic Chemistry 25(1960)1133 which is incorporated by reference.

The compounds of the invention are new chemical compounds of value asantifungal agents. More specifically, the compounds are active againstCandida albicans and Trichophyton mentagrophytes. Activity is determinedutilizing standard tube dilution tests in the absence of serum.

The invention is further illustrated by the following examples.

EXAMPLE 13,3'-(1,4-piperazinediyldimethylene)-bis[2-[(dimethylamino)methyl)]-1H-indole]

2-Methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole methiodide, 9.42 g., andpiperazine, 7.8 g., are refluxed in water, 700 ml. Solids appear inone-half hour. After one and one-half hours the the mixture is filteredto give 4.9 g. of a white solid, m.p. about 202° C. with decomposition.The filtrate is refluxed an additional hour, giving another 1.5 g. ofproduct. Recrystallization from a methanol-methylene chloride mixturegives a near-quantitative recovery of product, m.p. 202° withdecomposition (darkening at 175°). An analytical specimen was obtainedby recrystallization from tetrahydrofuran, m.p. 209°-211° withdecomposition.

EXAMPLE 23,3'-(1,4-piperazinediyldimethylene)-bis[2-[(n-butylmethylamino)-methyl]-1H-indole

The above named compound is obtained by utilizing the procedure ofExample 1 after substituting in the place of2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole methiodide, thefollowing compound; 2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indolemethiodide.

EXAMPLE 3Bis[2-[(n-butylmethylamino)methyl]-1H-indol-3-yl-methyl]-1,3-dihydro-2H-indol-2-one

Oxindole, 5.32 g., in dimethylformamide is added to a dimethylformamideslurry of fifty percent sodium hydride, 1.92 g., at 10° C. A solution of2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole methiodide indimethylformamide, 50 ml. is then added, and the resulting mixtureheated one hour on a steam bath. After stirring at room temperature forsixteen hours, the product is poured into ice water. The precipitate,18.4 g., is collected, as a slightly wet material containing somemineral oil. Two recrystallizations from acetonitrile returned 6.5 g. ofpure product, m.p. 127°-9° .

EXAMPLE 4Bis[2-[(n-dimethylamino)methyl]-1H-indol-3-ylmethyl]-1,3-dihydro-2H-indol-2-one

The above named compound is obtained by utilizing the procedure ofExample 3 after substituting in the place of2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole methiodide, thefollowing compound 2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]-indolemethiodide.

The hydrochloride salt of the above named compound is obtained bydissolving said compound in isopropanol and adding to it an ethersolution of hydrogen chloride.

Starting Materials a. 2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indolemethiodide

Methyl iodide, 37 ml., is added in a single portion to a warm,vigorously stirred solution of 2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 51.6 g., in dry acetone, 700 ml. A heavy crystallineprecipitate of the title compound starts to separate almost immediately,and after fifteen minutes of stirring is collected and washed thoroughlywith additional acetone, giving 80-85 g. The product is essentiallypure, and can be used directly.

b. 2-methyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole

2-Methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 1.7 g., and LiAlH₄,2.3 g., are heated in refluxing dioxane, 300 ml., for five hours. Themixture is cooled and carefully hydrolyzed with excess water. Solids arefiltered away and washed with dioxane, after which the filtrate isconcentrated to dryness giving 1.4 g. of a crude brown product, m.p.110°-120° C. Since the crude product is sensitive to air oxidation(darkens rapidly on standing), it is not further purified beforemethiodide preparation.

c. 2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one

1-Methyl-4-carbomethoxy-2,3-dioxopyrrolidine, 8.5 g., is heated on thesteam bath for about forty-five minutes to one hour in 150 ml. of atwenty percent aqueous hydrochloric acid solution. The resultingsolution is cooled to room temperature and filtered. Sodium acetate isnext added to neutralize the mixture to a pH of 4 to 5. Water is addedas necessary to keep most of the solids in solution. Phenylhydrazine,5.9 g., is then washed into the solution with a little methanol. A solidmaterial precipitates immediately and is collected and washed withwater. This crude phenylhydrazone is taken up in 100 ml. warm aceticacid and treated with 30 ml. concentrate hydrochloric acid. A vigorousreaction ensued after which the mixture is refluxed for ten minutes.Cooling precipitates crude title compound, 16.7 g., m.p. about 300°(dec.). Recrystallization from a large volume of methanol raised them.p. to 303°-6° (dec.).

d. 2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole methiodide

A slurry of 4.3 g. of 2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indolein dimethylformamide, 30 ml., is treated with methyl iodide, 4.3 g.After thirty minutes excess methyl iodide is removed using reducedpressure.

e. 2-n-butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole

2-n-Butyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one, 20 g., in drytetrahydrofuran, 400 ml., is added slowly to a slurry of LiAlH₄, 14 g.,in tetrahydrofuran, 250 ml. After refluxing twenty hours, the reactionmixture is hydrolyzed with 30 ml. of water, and filtered. After thesolvent is removed, one obtains 20.1 g. of a reddish-brown solid.Recrystallization from methanol, 200 ml., gives 11 g. of the titlecompound, m.p. 151°-2°.

f. 2-n-butyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one.

1-n-Butyl-4-carbomethoxy-2,3-dioxopyrrolidine, 107 g., [Southwick andOwellen, J. Org. Chem. 25(1960)1133] is heated to boiling in a mixtureof 600 ml. of a twenty percent aqueous hydrochloric acid solution andabout 100 ml. of ninety-five percent ethanol. Solids dissolved in aboutten minutes to give a yellow solution. After one hour of heating, theflask is cooled to about room temperature. Sodium acetate is then addedto neutralize the reaction mixture to a pH of 4-5. In addition about 500ml. of water is added during the neutralization to insure that mostmaterials will remain in solution. Phenylhydrazine, 54 g., is thenwashed into the stirred mixture with methanol, 20 ml. The phenylhydrazone starts to separate immediately, and is collected after tenminutes of cooling and stirring. The material is dissolved in 200 ml. ofacetic acid at 65° and treated with 100 ml. of concentrated hydrochloricacid. A strong exotherm takes the temperature up to about 110° whichcauses vigorous refluxing. Filtration of the cooled slurry yields 78 g.of the title compound, m.p. 215°-218° sinters at 210°. Dilution of thefiltrate with water gives additional product, 7 g., m.p. afterrecrystallization from methanol: 216°-218°.

We claim:
 1. A compound of the formula ##STR11## and pharmaceuticallyacceptable acid addition salts thereof wherein R¹ and R² are loweralkyl, R³ is hydrogen, lower alkyl, halogen or lower alkoxy and A is amolecular fragment of the formulae ##STR12## wherein R⁴ is hydrogen orlower alkyl.
 2. The compound of claim 1 having the name3,3'-(1,4-piperazinediyldimethylene)-bis[2-[(dimethylamino)methyl)]-1H-indole],and acid addition salts thereof.
 3. The compound of claim 1 having thename3,3'-(1,4-piperazinediylmethylene)-bis[2-[(n-butylmethylamino)methyl]-1H-indole],and acid addition salts thereof.
 4. The compound of claim 1 having thenamebis[2-[(n-butylmethylamino)methyl]-1H-indol-3-yl-methyl]-1,3-dihydro-2H-indol-2-one,and acid addition salts thereof.
 5. The compound of claim 1 having thenamebis[2-[(dimethylamino)methyl]-1H-indol-3-ylmethyl]-1,3-dihydro-2H-indol-2-one,and acid addition salts thereof.
 6. An antifungal pharmaceuticalcomposition comprising an antifugal effective amount of a compound ofclaim 1 and a pharmaceutical carrier.
 7. A method for treating a fungalinfection which comprises administering a pharmaceutical composition ofclaim 6.